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Action of cholinesterase inhibitors in patients’ brains
  1. K Herholz
  1. Correspondence to:
 K Herholz
 Department of Neurology, University of Cologne, and Max-Planck-Institute for Neurological Research, Gleuler Str. 50, 50931 Cologne, Germany; karl.herholzpet.mpin-koeln.mpg.de

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Cholinesterase inhibitors in patients’ brains

Cholinesterase (ChE) inhibitors are the only class of drug that have consistently shown improvement in cognitive function in patients with mild to moderate Alzheimer’s disease. Unfortunately, improvement is generally rather small.1 Recent clinical trials have caused considerable controversy about their actual benefit and indications. On one hand, some studies suggest more extensive use because improvement of cognitive function has also been observed in vascular dementia, dementia with Lewy bodies, and Parkinson’s disease with dementia. However, on the other hand a recent study in community resident patients with mild to moderate Alzheimer’s disease concluded that benefits were “below minimally relevant thresholds.”2

On the background of this confusing situation, studies are particularly welcome that provide clues as to how ChE inhibitors exert their moderate effect in patients and how we could increase their efficacy. In this issue, such information is provided in a study by Bohnen et al,3 (see page 315) which measured the actual inhibition of cortical acetylcholine esterase (AChE) activity by donepezil in vivo and studied the correlation of the degree of inhibition with the cognitive effects. Several observations were made that indicate directions for improving therapy.

The inhibition of cortical AChE activity by donepezil at the recommended dose of 10 mg daily was rather low (on average 16–24% depending on cortical regions) and it varied considerably among patients. Although somewhat higher values had been measured with a slightly different tracer by other authors cited in the paper, inhibition of human cerebral AChE is much less than observed in peripheral blood,4 which is in contrast to findings in rats.5 Thus, dosage, pharmacokinetics, or specific binding of the drug to human cerebral AChE appear to be suboptimal, and this had not become evident during preclinical and clinical phases of drug development and testing.

The study also indicates that the degree of cerebral AChE inhibition makes a clinical difference because it was significantly correlated with measures of executive function and attention. This indicates that it could indeed be worthwhile to increase inhibition in selected patients, e.g. by higher dosage if side effects permit. It is expected that similar positron emission tomography (PET) studies will be performed to measure inhibition of cerebral butyrylcholine esterase (BChE) for selection and development of drugs that achieve higher effective levels of acetylcholine by additional inhibition of this degradation pathway.6

Another interesting aspect is that the relatively small inhibition effects were observed in temporal and parietal association cortex—structures that are thought to be of pivotal importance for episodic and semantic memory—that did not benefit significantly from treatment in this and other studies. One would wish to see similar studies with other ChE inhibitors to determine whether this is a property of the entire class of drugs.

It is gratifying that such direct in vivo assessments of pharmacological action are happening now, which means that we do not depend solely on large trials with clinical outcome measures that are, of course, of utmost clinical importance but often tell very little about the mechanisms that explain interindividual variation. One can hope that this will ultimately provide rational means to improve treatment of individuals, which is in the primary interest of patients and doctors.

Cholinesterase inhibitors in patients’ brains

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  • Competing interests: none declared

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